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ALLOPREGNANOLONE PROMOTES CHOLESTEROL AND AMYLOID-BETA CLEARANCE MECHANISMS: ASSESSMENT OF A REGENERATIVE THERAPEUTIC FOR ALZHEIMER’S DISEASE

      Background

      We aim to develop Allopregnanolone (Allo) as the first regenerative therapeutic for Alzheimer’s disease (AD). Allo reduces amyloid-beta (Aβ) and neuroinflammatory burden while promoting cholesterol homeostasis via mechanisms that promote the liver-X-receptor (LXR) and pregnane-X-receptor (PXR).

      Methods

      Crystal structures for PXR/RXRα, LXRβ, and LXRα/RXRβ were accessed from the Protein Data Bank. Docking calculations were carried out using DockingServer. Lipoprotein Signaling and Cholesterol Metabolism gene array and Western blots for protein expression were performed using hippocampus and cortex tissue from 3xTgAD mouse.

      Results

      The Ki for Allo (LXRβ 0.12 μM, PXR 1.17 μM) was comparable to known ligands for each receptor indicating that the configuration and composition is compatible for each of the receptors. Allo’s established free energy of binding (LXRβ -9.44 kcal/mol, PXR -8.49 kcal/mol) signified favorable protein-ligand associations. Allo decreased expression of OLR1 and PCSK9 that promote cholesterol efflux and reduce inflammation. Allo increased the gene expression of CXCL16, LRP6, HMGSC1, and Cyp51 involved in stimulation of the PI3K/Akt/Erk and Wnt pathways and cholesterol synthesis pathway. STAB2 and Idi2 increased and to reduce inflammation signals. Allo also decreased PCSK9 and AKR1D1 genes to promote cholesterol efflux while decreased ANGPTL3 provides a mechanism for reducing plasma cholesterol levels. Allo increased LXRβ, LDL-R, SORL1, ABCA1, Cyp46a1, and decreased NF-κB protein expression in 3xTgAD male mice.

      Conclusions

      Collectively, increased expression of ABCA1, APOE, LDL-R and SORL1 support the hypothesis that Allo treatment promotes the clearance of cholesterol and Aβ. Allo activation of LXR provides a plausible therapeutic strategy to increase Aβ degradation and clearance by utilizing ABCA1 and LDL-R to remove Aβ. Earlier analysis indicated that Allo increases LXR, PXR, and HMG-CoA-R protein expression (Chen et al., 2011). The results suggest that Allo plays a role in cholesterol homeostasis by directly or indirectly activating LXR and PXR leading to the induction of beneficial genes and pathways to reduce Alzheimer’s pathology. Additional genes promoting cholesterol homeostasis were altered with Allo treatment to protect the brain from inflammation, apoptosis, decrease Aβ, and to regulate cholesterol clearance. Research supported by NIA U01 AG031115; NIA U01 AG047222; and UF1 AG046148 to RDB.